Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C9-C10 position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters.
A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). A single SCD gene, SCD1, has been characterized in humans. SCD1 is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety. A second human SCD isoform has recently been identified, and because it bears little sequence homology to alternate mouse or rat isoforms it has been named human SCD5 or hSCD5 (PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety).
The biochemical roles of SCD have been known in rats and mice since the 1970's (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-112; de Antueno, R J, Lipids (1993), Vol. 28, No. 4, pp. 285-290). More recently, it has also been directly implicated in various human disease processes, including type II diabetes, insulin resistance, obesity, dyslipidemia, hypertriglyceridemia, acne, inflammation, metabolic syndromes, and cancer.
Patients with type II diabetes produce insulin, but lose the ability to respond to insulin, i.e., the patients have decreased insulin sensitivity. Ntambi, J. M. et al., Proc. Natl. Acad. Sca, (Aug. 20, 2002), Vol. 99, No. 17, pp. 11482-6, shows that mice with disrupted SCD-1 activity have increased insulin sensitivity (first paragraph, p. 11482). It further shows that SCD-1 knock-out mice exhibit improved glucose tolerance and a greater response to glucose lowering effects of insulin, when compared with the wild-type mice (p. 11484). These results suggest that inhibition of stearoyl-CoA desaturase-1 activity can increase insulin sensitivity, thereby preventing or treating Type II diabetes.
In a study by Sjogren, P. et al., Diabetologia, (2008), 51(2):328-35, involving 294 men, it was shown that elevated SCD activity within adipose tissue is closely coupled to the development of insulin resistance. In addition, Warensjo, E. et al., Obesity, (2007), 15(7):1732-40, shows that, in a study involving 1143 men, genetic variations, e.g., single nucleotide polymorphisms, in the SCD-1 gene are associated with insulin sensitivity. Together, the data obtained from animal and human studies support the idea that elevated SCD activity is linked to insulin resistance and inhibition of SCD-1 activity may lead to increased insulin sensitivity. Therefore, the SCD-1 inhibitor compounds may be used in treating/preventing animals or humans for type II diabetes and/or for increasing insulin sensitivity.
Park, E. I. et al., J. Nutr. (1997), Vol. 127, pp. 566-573, show that mice provided with a diet that lowered the expression of SCD-1 had lower body weights and lower serum concentrations of total cholesterol, triglycerides and HDL cholesterol. Furthermore, Ntambi et al, cited above, showed that loss of SCD-1 function (activity) protects mice from gaining weight from a high-fat diet. Importantly, Hulver, et al., Cell Metabolism, (2005), 2:251-61, shows that SCD-1 is robustly up-regulated in skeletal muscle from extremely obese people. Thus, SCD-1 inhibitors may be used to treat obesity.
In addition, SCD-1 inhibitors may be used to treat dyslipidemia and hypertriglyceridemia by lowering triglyceride, LDL and VLDL serum levels. WO 01/62954 discloses an animal model for testing the claimed compounds' effectiveness in lowering triglyceride, LDL and VLDL serum levels (see Example 1) and demonstrates the correlation between SCD-1 activity in humans and the levels of serum triglycerides (see Example 2). Consistently, as noted by Miyazaki, M. et al., Journal of Lipid Research (2001), Vol. 42, pp. 1018-1024, triglyceride synthesis can be dramatically reduced in the liver of SCD-1 knock-out mice fed a lipogenic diet, as compared with the normal mice. See also, Miyazaki, M. et al., J. Biol. Chem. (2000), Vol. 275, No. 39, pp. 30132-30138. Furthermore, Attie, A. D. et al., Journal of Lipid Research (2002), Vol. 43, pp. 1899-1907, shows that SCD activity may be rate-limiting in triglyceride production in a wide array of dyslipidemias. Savransky, et al., Cir. Res., (2008), 103:1173-80, also shows that down-regulation of SCD-1 gene by antisense oligonucleotides can attenuate the chronic intermittent hypoxia-induced dyslipidemia and atherosclerosis in mice. In humans, Savransky, et al., Cir. Res., (2008), 103:1173, further shows that the expression levels of SCD gene are correlated well with dyslipidemia in patients exhibiting chronic intermittent hypoxia. These observations demonstrate that the induction of triglyceride synthesis is highly dependent upon the expression of the SCD-1 gene. Therefore, the SCD-1 inhibitor compounds may be useful in treating hypertriglyceridemia by lowering triglyceride, LDL, and VLDL serum levels and in treating dyslipidemia in a human subject.
SCD-1 inhibitor compounds may be used to treat metabolic syndrome. The term “metabolic syndrome” is a recognized clinical term. Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes, and may be used to describe a condition comprising at least one of type II diabetes, impaired glucose tolerance and insulin resistance, together with one or more symptoms of hypertension, obesity, hypertriglyceridemia, low HDL and microalbuminemia. In other words, the term “metabolic syndrome” may be used to describe a cluster of metabolic abnormalities. Thus, disorders like dyslipidemia, hypertension and obesity may be components of the metabolic syndrome and inhibition of SCD-1 activity can be a therapeutic treatment for each of these disorders individually or collectively. Given that SCD-1 is a key regulator of fatty acid metabolism and insulin action (see Ntambi, J. M. et al., Journal of Lipid Research (1999), Vol. 40, pp. 1549-1558), a compound that inhibits SCD-1 activity can impact more than one component of the metabolic syndrome and may be useful in treating this disease.
SCD-1 inhibitors may also be used to treat acne. Zheng et al., Nat. Genet. (1999) 23:268-270, show that rodents lacking a functional SCD-1 gene have changes to the condition of their eyes, skin and coat thereby reducing the excessive sebum production that typically results in the formation of acne. As noted by Miyazaki et al., J. Nutr. (2001), Vol. 131, pp 2260-68, SCD-1 knock-out mice developed cutaneous abnormalities and atrophic sebaceous and meibomian glands compared to normal mice. Modulation of SCD activity can be of importance in the treatment of disease states that are associated with changes in the lipid composition in the sebaceous and meibomian glands and their lipid secretions as well as changes in the composition of circulating lipids that impact these tissues (see Ntambi J et al., J. Lipid Res. (1999), (40):1549) and US Patent Publication No. 2005/0151018). These observations demonstrate that reduction of the sebum production can be effected by the inhibition of SCD-1. Therefore, by virtue of their ability to inhibit SCD-1 activity, SCD-1 inhibitors may be useful in treating acne in humans.
In a large population-based cohort study involved 767 men, Petersson, H., et al., Br. J. Nutr. (2008), 99(6):1186-9, shows that inflammation, as indicated by an increased concentration of serum C-reactive protein (CRP), is positively associated with SCD-1 activity. The same group of investigators further confirms their previous observation by showing that SCD-1 index is positively correlated with CRP, and thus inflammation, in 264 older men and women aged 70 (Petersson, H., et al., Atherosclerosis. (2008), July 1, Epub ahead of print). Therefore, SCD-1 inhibitors may be used to treat inflammation.
SCD-1 inhibitors may also be used to treat cancer. Saturated (SFA) and monounsaturated fatty acids (MUFA), the most abundant fatty acid species, are involved in the regulation of various cellular functions, including proliferation, programmed cell death (or apoptosis), and lipid-mediated cytotoxicity. High levels of MUFA have been associated with several types of cancers. Because SCD regulates the conversion of SFA into MUFA, SCD may be involved in tumorigenbesis. Indeed, increased expression of SCD gene has been found in colonic and esophageal carcinoma, and in hepatocellular adenoma (Li, J. et al., Int. J. Cancer, (1994), 57:348-52); and in chemically induced tumors (That, S. F., et al., Carcinogenesis (2001), 22:1317-22). Consistently, both SCD gene expression and fatty acid synthesis are found higher in the transformed human lung fibroblasts than that of their normal counterparts (Scaglia, N. et al., Biochim. Biophys. Acta, (2005), 1687:141-51). Scaglia, N. et al., J. Biol. Chem., (2005), 280:25339-49, and Scaglia, N. et al., Int. J. Oncol., (2008), 33:839-50, further shows that down-regulation of SCD-1 gene, using antisense approach, in the transformed human lung fibroblasts or in a human lung adenocarcinoma cell line (A549) reverses two hall-marks of neoplastic transformation, i.e., proliferation and anchorage-independent growth. In addition, increased apoptosis and deactivation of cancer-related genes, e.g., AKT and GSK3β, are found in the SCD-1 down-regulated A549 cells. Importantly, the reduction of SCD-1 gene expression in human lung cancer cells significantly delays the formation of tumors and reduces the growth rate of tumor xenografts in mice. These data demonstrate the anti-tumor activity of agents that can reduce SCD-1 expression and/or inhibit SCD-1 activity in human cancer cells. Therefore, by virtue of their ability to inhibit SCD-1 activity, SCD-1 inhibitors may be useful in treating cancer in humans.
The present invention presents new classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.